Effects of an Angiotensin II Receptor Antagonist, CV-11974, on Angiotensin II-Induced Increases in Cytosolic Free Calcium Concentration, Hyperplasia, and Hypertrophy of Cultured Vascular Smooth Muscle Cells

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The effects of CV-11974, a potent nonpeptide antagonist of the angiotensin II (All) type-1 receptor (AT1), on cytosolic free calcium concentration ([Ca2+ ]i), hyperplasia, and hypertrophy of cultured vascular smooth muscle cells (VSMC) from rat aorta were studied. [Ca2+ ]0 was measured by fura 2, and hyperplasia and hypertrophy were determined by incorporation of [3H]thy-midine and [3H]leucine, respectively. CV-11974 had no effect on [Ca2+ ]i itself, but suppressed 10-7M All-induced increase in [Ca2+ ]s dose dependently at concentrations from 10-10M and completely at 10-7 M. CV-11974 suppressed both Ca2+ release from intracellular Ca2+ stores and Ca2+ influx from the extracellular space. However, CV-11974 had no effect on the increases in [Ca2+ ]; induced by prostaglandin F2α (PGF2J, a potent vasoconstrictor, or ionomycin, a Ca2+ ionophore. These results indicate that the suppressive effects of CV-11974 act on the binding of AII and its specific receptors. AH 10-7M increased the synthesis of DNA and protein to 1.5 and 1.7 times the control values, respectively. CV-11974 had no effect on synthesis of DNA or protein, but suppressed the All-stimulated synthesis of DNA and protein dose dependently at concentrations s10-8 and 10-10M, respectively and completely at 10 -6 M. These results indicate that All increases [Ca2+ ]i and synthesis of DNA and protein in VSMC through activation of AT,. CV-11974 showed no partial agonistic effects on AH. Thus, CV-11974 may act not only as an antihypertensive agent, but also as an inhibitor of vascular injury stimulated by AH.

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